Alcoholic beverages are consumed around the world as an acceptable part of many recreational and ceremonial activities. Low-to-moderate use of alcohol may facilitate socialization, as it reduces anxiety and has a disinhibiting effect on social behaviors. Compared to other drugs of abuse, relatively large amounts of alcohol are required to produce physiological effects. Consider that the average drink contains 14 grams of ethanol, 1 whereas a tobacco cigarette or a tablet of oxycodone hydrochloride contains only milligram quantities of the active substance. The US National Institute on Alcohol Abuse and Alcoholism defines “,heavy drinking”, as consuming more than four drinks a day or 14 drinks a week for males, and consuming more than three drinks a day or seven drinks a week for females. It is estimated that one in four heavy drinkers have alcohol-related problems, such as dependence. 1 Alcoholism pathophysiology.
Addiction treatment trials often use the Diagnostic and Statistical Manual of Mental Disorders (Text Revision), 4th edition (DSM-IV-TR) definition of alcohol use disorders ([AUD] abuse or dependence) to define study participants. The DSM-IV definition of alcohol dependence requires significantly harmful impact caused by at least three out of seven target conditions within a single year. These dependence symptoms include tolerance, withdrawal, increased amounts of alcohol consumed over time, ineffective efforts to reduce use, interference with personal or professional life, significant amount of time spent obtaining, using, and recovering from alcohol, or continued use of alcohol despite harmful sequelae. 2 Alcohol abuse is defined broadly and requires the presence of at least one of the four abuse criteria for diagnosis.
The DSM-5, which was released in May 2013, has combined criteria for alcohol dependence and abuse into a single term (AUD). Craving was added as a diagnostic criteria and at least two target conditions are now required for diagnosis of AUD. 3 New International Statistical Classification of Diseases and Related Health Problems (ICD) 10 codes that correspond to DSM-5 will be used beginning in October 2014. The majority of clinical trials in this review include subjects with DSM-IV alcohol dependence diagnosis.
Although approved pharmacologic treatment options for patients with AUD are limited in number, recent trials describe a host of alternative approaches to reducing alcohol consumption. These include the use of antipsychotics, antidepressants, anticonvulsants, and others, under the rationale that these drugs target the neurotransmitter systems that have been shown to undergo changes with chronic exposure to alcohol. This review describes current evidence for the clinical use of a broader range of pharmacotherapies in AUD, along with available information on patient characteristics (eg, genetic, demographic, behavioral) that may predict positive outcomes of treatment.
Neurobiology and pathophysiology of AUD
The acute and chronic effects of alcohol on brain physiology have been well studied and help to rationalize the investigation of psychotropic drugs in the treatment of AUD. In particular, neurotransmitter pathways involved in learning and reward have proven to be effective targets, based on the mechanisms of action of two currently approved AUD drugs, acamprosate and naltrexone. Other compounds under current investigation similarly produce effects by targeting monoamine (eg, serotonin [5-HT], norepinephrine, dopamine) or amino acid (eg, glutamate, γ,-aminobutyric acid [GABA]) neurotransmitters.
Alcohol neuroadaptation and reward
Alcohol, like other addictive drugs, stimulates release of the neurotransmitter dopamine from cells originating in a region of the brain called the ventral tegmental area (VTA). 4 The VTA is a component of a neuronal circuit called the mesolimbic dopamine system that has been associated with behavioral motivation and reward. Following exposure to alcohol, dopamine released into the nucleus accumbens (NAc) and prefrontal cortex has been postulated to reinforce drinking behaviors or make the experience of drinking more salient. Recent reviews of the neurobiological literature have described evidence that neuronal plasticity and metaplasticity in the mesolimbic system can promote reward-based learning and the development of addiction. 5 Whereas alcohol does not appear to selectively bind dopamine receptors, its effects on dopamine release are likely mediated through interactions with other neurotransmitter systems, such as glutamate, GABA, corticotropin-releasing factor, and 5-HT, as well as through interactions with the endogenous opioid system (eg, endorphins, enkephalins). 6
Electrochemical activation of neurons is controlled by a balance between excitatory and inhibitory neurotransmitters. Acutely, alcohol inhibits the flow of ions through N-methyl-D-aspartate (NMDA)-type glutamate receptors and enhances the activity of GABA receptor channels, producing an overall inhibitory effect on neurons. 7 Chronic exposure to alcohol promotes neuroadaptive responses that increase the potential excitability of neurons through upregulation or trafficking of NMDA receptors. 8 Changes in glutamate signaling pathways associated with chronic exposure to alcohol may enhance the response to cues associated with drinking. Plasticity at glutamatergic synapses on dopamine neurons exists in many forms and may regulate how efficiently drug-related events and actions affect vulnerability to developing addiction. 5 Furthermore, changing the balance between glutamate and GABA signaling establishes a state of hyperexcitability that is manifest upon cessation of drinking and that may contribute to the negative symptoms of alcohol withdrawal. 9 Changes in the GABA system contribute to the anxiogenic and aversive effects of alcohol withdrawal and can persist over long periods of abstinence from alcohol. The desire to relieve anxiety and negative sensations of withdrawal can contribute to relapse to drinking and lead to the repetitive and compulsive behaviors that characterize alcohol dependence. 9
Pharmacologic strategies to reduce drinking in patients with AUD may attempt to correct the imbalance between excitatory and inhibitory pathways, and relieve the intense craving for alcohol brought about by neuroadaptation. Alternatively, compounds that target reward pathways may compensate for the plasticity in dopamine signaling that enhances the drinking experience of patients with AUD.
Alcoholic cirrhosis pathophysiology
In spite of increasing knowledge of the neurobiological disturbances caused by habitual drinking, a common etiological cause for AUD has not been established. Furthermore, the complex interplay of genetic and environmental factors predisposing an individual to the development of AUD exacerbates the search for pharmacologic treatment options that are generally effective across patient populations. 10
Pathophysiological consequences of alcohol use
Even in otherwise healthy individuals, alcohol is toxic to most organ systems at doses above one to two drinks per day. 11 Long-term exposure to alcohol generally increases the risk of damage to the gastrointestinal, cardiovascular, immune, nervous, and other systems. Cellular toxicity can be initiated by the metabolism of ethanol and subsequent accumulation of acetaldehyde, a metabolite that can damage intracellular proteins and induce cell death through apoptosis. 11 Additionally, changes in the oxidation–,reduction state of a cell following substantial ethanol metabolism can have an impact on cellular respiration and the metabolism of fats in both animals and humans. 12
Alcohol can promote gastrointestinal bleeding through inflammation of the esophagus and stomach, or through vomiting that can damage the gastrointestinal mucosa. Acute pancreatitis is more prevalent in alcoholics than in the general population and can progress to chronic disease or pancreatic cancer with prolonged exposure. 13 Accumulation of fat in the liver as a result of decreased oxidation of fatty acids and other metabolic changes can progress to fatty liver disease, alcohol-induced hepatitis, and cirrhosis. 14
Low-to-moderate alcohol consumption (one to two drinks per day) causes peripheral vasodilation and decreases contractility of the heart, resulting in a mild decrease in blood pressure. 15 Changes in clotting mechanisms or increases in high-density lipoprotein in alcohol users who typically have one drink per day may even confer a cardioprotective effect. 16 However, consuming three or more drinks per day is a factor in mild-to-moderate hypertension and heavy drinkers are at increased risk for coronary artery disease and cardiomyopathy. The effects of heavy drinking can range from left ventricular impairment and arrhythmia to heart failure as a result of limited contractility of heart muscle. Binge drinking (eg, a single exposure to 90 mL of 80-proof whiskey) can produce atrial or ventricular arrhythmias, even in individuals who have no other evidence of heart disease, a syndrome known as “,holiday heart.”, 17
Alcohol-dependent individuals may experience peripheral neuropathy characterized by tingling or numbness, especially in the hands and feet. A progressive neurologic syndrome that affects gait and stance, often accompanied by nystagmus, can result from atrophy of the cerebellum due to alcohol toxicity. 18 Less common are neurologic syndromes that result from thiamine deficiency secondary to heavy drinking: Wernicke’,s syndrome consists of encephalopathy, uncoordinated muscle movement, and eye muscle weakness, and Korsakoff’,s syndrome is characterized by amnesia.
Pharmacotherapy: approved medications for AUD
Pharmacologic strategies for treating alcohol dependence include generating an aversive physiological reaction to alcohol to mask positive subjective effects and administering medications that block alcohol reinforcement. Medications that target the reward pathways in the brain have been suggested to normalize adaptations to chronic alcohol exposure and reduce craving for alcohol. 7 Other strategies aim to reduce negative symptoms of alcohol withdrawal that may promote relapse drinking by restoring the balance between inhibitory and excitatory neurotransmitter pathways. 7 Three medications are currently approved by the US Food and Drug Administration for the treatment of alcohol dependence in adults: disulfiram, acamprosate, and naltrexone. Nalmefene is approved for alcohol dependence in Europe.
Pharmacotherapy: non-approved medications for AUD
A variety of non-approved medications have been studied in the treatment of AUD. Medications like disulfiram and naltrexone have been associated with hepatic toxicity. This can be an issue with chronic drinking, as alcohol is associated with hepatotoxicity and 55% of deaths associated with alcohol are the result of liver disease. 49 Acamprosate should be avoided in patients with severe renal impairment. 50 Additionally, these medications are not effective in all patients for an indeterminate period of time, 51 leading clinicians to seek additional options for the treatment of AUD.
Common measurements to determine the efficacy of medications for AUD include: percentage of drinking days, total amount of drinking, relapse, abstinence, cravings, and brain activation in the reward pathways of the brain.
Many published studies of non-approved medications included patients on psychotropic agents (eg, antipsychotics, antidepressants, anticonvulsants), suggesting the presence of a comorbid psychiatric illness and dual diagnosis of AUD with a mood or thought disorder. Dual diagnosis is an important and challenging issue, which can, however, introduce a number of variables that can lead to relapse. Clinical trials in patients with uncontrolled comorbid psychiatric diagnoses are not included in this review but can be found in other publications. 52, 53
Antipsychotics are used for the treatment of schizophrenia and bipolar disorder and as adjunctive treatment for depression and autism. They block various dopamine receptors, and the second-generation antipsychotics are unique in that they also block 5-HT
receptors. Due to dopamine’,s implication in the reward pathways associated with AUD, these medications are targets for current research.
The majority of antidepressants studied in alcohol dependence use selective 5-HT reuptake inhibitors (SSRIs). These work by blocking the reuptake of 5-HT, allowing increased agonism of 5-HT receptors. 5-HT agonists have shown reduction in alcohol consumption in animal studies, 70 and, due to these findings, may be a future option for AUD treatment.
Anticonvulsants are used for seizure disorders and several have indications for chronic pain conditions and mood stabilization. They have a variety of mechanisms, including blockage of sodium channels, enhancing GABA, antagonizing glutamate receptors, and blocking calcium channels.
Disulfiram, naltrexone, acamprosate, and nalmefene all have benefits in the treatment of AUD. Considering the potential for treatment failure with approved pharmacological options or the inability to use a medication due to comorbid health conditions, a number of medications have been studied in AUD. For example, in the presence of a failed response to naltrexone or a contraindication (current opioid withdrawal) to its use, aripiprazole 57 and topiramate 92 both appear to be equal to naltrexone in efficacy for AUD. Perhaps the continued exploration of non-approved medications will result in the identification of a drug or combination of drugs that demonstrates generalized effectiveness in all AUD patient types.
Pancreatitis alcoholism pathophysiology
Alternatively, heterogeneity of AUD patients and the complex etiology of the disease may preclude the discovery of such a drug. Varying patterns of consumption and differences in onset of drinking have defined AUD patient subtypes that respond differently to pharmacotherapy. Reported outcomes in subpopulations of study cohorts have followed a range of demographics, including sex and genetic background. Recognizing trends in current reports and strengthening associations between AUD subtypes and treatment outcomes with new studies may provide clinical guidance to prescribers in the near future. For example, an individual’,s drinking goal (eg, controlled drinking, conditional abstinence, complete abstinence) established prior to treatment has been shown to be highly associated with clinical outcome, validating the importance of patient motivation for behavioral change. 131 Clinical outcomes and drinking behavior just prior to treatment have also been shown to associate with medication effect. Acamprosate is slightly more efficacious in promoting abstinence than naltrexone, and it has a larger effect size in patients who have undergone detoxification. 132 Naltrexone is slightly more efficacious in reducing heavy drinking than acamprosate, and it is associated with a larger medication effect in patients who enter treatment after a period of lead-in abstinence. 132 Therefore, a patient’,s drinking goals and current drinking status, as well as the intended clinical outcome, should be determined prior to treatment.
With regard to sex, although women with AUD enter treatment earlier in the course of the disease than men, 133 clinical studies of pharmacologic AUD treatment tend to be comprised of mostly male patient populations. Treatment responses have been suggested in some cases to be better in men than women (eg, naltrexone, 41 citalopram, 72 and sertraline 75 ), but a recent meta-analysis of over 50 naltrexone and acamprosate trials found no effect of sex on response to treatment. 35 Although flupenthixol decanoate increased relapse rates among AUD patients, the risk was significantly lower in women than in men. 67 Further AUD treatment studies that separate male and female populations are warranted.
Other examples of patient-specific criteria that might guide clinical decisions include the use of gabapentin in patients with comorbid insomnia, 85 prazosin in patients who drink secondary to a stress response, 126 and varenicline in patients who smoke, 127, 128 and data suggest olanzapine’,s usefulness in patients with genetic predispositions related to the dopamine receptor gene. 58
The influence of genetic background on patient response has been exemplified by the interaction between naltrexone response and polymorphisms in the μ, opioid receptor gene OPRM1. In a review of the studies that included genetic information, Chamorro et al report that AUD patients who carry the A118G allele demonstrate lower rates of relapse to heavy drinking, with no change in abstinence. 134 Evidence for a genetic influence on treatment response has also been reported for disulfiram, 27 olanzapine, 58 and ondansetron. 135 As genetic testing becomes more cost-effective, it may represent a feasible strategy to tailor AUD treatments to an individual patient’,s disease. The use of genetic information has become standard practice in other areas of medicine, including anticoagulation and oncology.
Research with well-designed studies will continue to be a necessity in the area of pharmacologic treatment for AUD. Based on the current state of AUD treatment research, it appears unlikely that a single agent or combination regimen will prove to be effective in all patients with AUD. Instead, clinicians may be obligated to match medication strategies to individuals or AUD subtypes, and this approach demands stronger evidence of treatment efficacy in particular patient groups.